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How many Immunotherapies for advanced hepatocellular carcinoma?
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How many Immunotherapies for advanced hepatocellular carcinoma?
Hepatocellular carcinoma is the second most common lethal tumor species worldwide, and the case fatality rate is high.
The clinical symptoms of early liver cancer are not obvious, 70% to 80% of patients are in the advanced stage when they see a doctor, the prognosis is poor and there is a lack of effective treatments  .
In the first-line treatment of unresectable liver cancer, the NCCN guidelines recommend a variety of treatment options, including atilizumab combined with bevacizumab, sorafenib, lenvatinib, nivolumab and FOLFOX ( Oxaliplatin + leucovorin + fluorouracil) chemotherapy, etc.  .
As immunotherapy has made great progress in various cancers, the academic community has also launched an attempt to treat hepatocellular carcinoma in recent years.
At ESMO Asia Academic Week in 2021, Professor Stephen L. Chan of the Chinese University of Hong Kong shared the frontier information about immunosuppressive agents that have been approved and are being developed in the field of hepatocellular carcinoma.
Advanced Hepatocellular Carcinoma Immunotherapy Frontier
Hepatocellular carcinoma (HCC) is a common malignant tumor, and it is the second most common cause of tumor-related death worldwide. It has caused hundreds of thousands of deaths in 2020  .
The tumor microenvironment plays a vital role in the occurrence and development of diseases, and the response of tumors to treatment is also affected by it.
In the HCC tumor microenvironment, immune cells such as regulatory T cells (Tregs), bone marrow-derived suppressor cells (MDSC), and some cytokines can cause immunosuppression and tumor escape, thereby promoting the occurrence and development of liver cancer; Depletion of toxic T cells also impairs the immune system’s ability to eliminate malignant cells.
Therefore, if immunotherapy can be used to boost the patient’s immune system function, it will help the treatment of unresectable advanced HCC.
In the past few decades, the targeted drugs sorafenib and lenvatinib have been approved successively in the HCC field, and they have been included in recommended treatments by many clinical guidelines around the world; however, after targeted therapy is resistant, patients with advanced HCC have Treatment options are still limited.
In recent years, with the introduction of immune checkpoint inhibitors into the clinic, the treatment of advanced tumors has more options; the academic community is also committed to trying to apply immunotherapy to the treatment of advanced HCC  .
The NCCN (National Comprehensive Cancer Network) guidelines updated in 2021 further emphasized immunotherapy strategies, and moved lenvatinib and sorafenib in the category 1 recommendation from the previous “preferred programs” to “other recommended programs” “, Atelizumab combined with bevacizumab (“T+A”) is used as the only guideline recommended for first-line treatment (Class 1 recommendation).
Review of major studies on immune checkpoint inhibitors in the treatment of HCC
The first clinical study of immune checkpoint inhibitor for HCC is Tremelimumab, which targets CTLA-4.
This clinical study published by Bruno Sangro et al. in 2013 included patients with HCC and chronic hepatitis C  , aiming to evaluate the efficacy and safety of trimelimumab in the treatment of this group.
Most of the patients enrolled were in the advanced stage of the disease, and 43% of the patients had liver function changes (Child-Pugh grade B).
Subsequently, the patient received intravenous injection of trimelimumab every 90 days at a dose of 15 mg/kg body weight per treatment until the disease progressed or the toxicity became intolerable.
The results of the study showed that trimelimumab treatment is safe; the partial remission rate was 17.6%, and the disease control rate reached 76.4%.
With the birth of PD-1/PD-L1 drugs and the positive results achieved in other tumor types, anti-PD-1 therapies have also been explored in the field of HCC. In the Phase I/II open-label, dose-escalation single-arm trial CheckMate 040  , 262 eligible patients with advanced liver cancer who had previously received or had not received sorafenib treatment received nivolumab treatment.
The results Shows that the incidence of treatment-related adverse events does not seem to be dose-related, and the overall tolerance is good. In the patients who received 3 mg/kg body weight of nivolumab during the dose expansion phase, the objective response rate was 20%; in the patients who received nivolumab during the dose escalation phase, the objective response rate was 15%.
Controllable safety and long-lasting objective remission levels indicate that nivolumab has the potential to treat HCC.
The phase II KEYNOTE-224 study evaluated the effect of pembrolizumab in the treatment of HCC  .
The enrolled HCC patients had previously received sorafenib treatment, and the drug was discontinued due to disease progression or intolerance; after enrollment, they received 200 mg pembrolizumab intravenously every 3 weeks for two years until the disease Discontinuation of the drug due to progression, intolerable toxicity, or other reasons.
As of the data cut-off date, 17 of the 104 subjects were still receiving treatment; the objective response rate was 17%, and the best response was 1 case (1%) complete remission and 17 cases (16%) partial remission.
The most common adverse reaction is an increase in the concentration of transaminase, which is generally well tolerated. Pembrolizumab is currently undergoing further evaluation in two phase III clinical studies as a second-line treatment for HCC.
Based on the above results, both the liver cancer indications of nivolumab and pembrolizumab have obtained accelerated approval from the US FDA.
In comparison, the two drugs have good efficacy and safety in the treatment of HCC, and follow-up may need to carry out head-to-head comparisons and confirm their survival benefits in larger-scale clinical studies.
However, positive disease remission data does not represent an improvement in the ultimate survival level. The phase III KN240 study for pembrolizumab has previously failed  .
The study compared the efficacy of pembrolizumab and placebo in the second-line treatment of sorafenib-treated patients. Statistically significant overall survival (OS) benefit.
The Phase III CheckMate-459 study of Nivolumab also faced the same failure results  , and the primary endpoint of the study did not achieve statistical differences.
It is worth mentioning that nivolumab has now been withdrawn as a monotherapy for the accelerated approval of HCC patients who have previously received sorafenib.
Attempt of immunosuppressant combination therapy in HCC
Based on the results of existing studies, the PD-1/PD-L1 inhibitor single-drug regimen is considered to be no better than sorafenib in the first-line regimen, and the survival benefits obtained in the second-line regimen are relatively limited.
Therefore, in order to enhance the effect of immunotherapy in advanced HCC, clinical trials have begun to combine treatment strategies.
In the first-line treatment, the Phase III IMbrave150 study evaluated the effect of atelizumab targeting PD-L1 in combination with bevacizumab versus sorafenib  .
The study showed that compared with the sorafenib treatment group, the death hazard ratio of the atelizumab combined with bevacizumab treatment group was 0.58, and there was a significant improvement in survival (12-month overall survival rate: 67.2% vs. 54.6%; median progression-free survival: 6.8 months vs. 4.3 months).
In terms of safety, the incidence of adverse events in both groups was ≥10%, and no bleeding risk was found; in the atelizumab combined with bevacizumab treatment group, 15.2% of patients had grade 3 or 4 high Blood pressure and other serious side effects are not common; it is recommended that patients undergo endoscopic screening.
Another randomized, open-label Phase II/III study in China evaluated the PD-1 inhibitor Sintilizumab in combination with the bevacizumab biosimilar IBI305  as compared to the first-line treatment of sorafenib The effect of advanced HCC.
Among the patients enrolled in the study, 571 patients were randomly assigned to receive sintilimab combined with IBI305 treatment (n=380) or sorafenib (n=191).
Interim analysis showed that the overall survival of patients in the sintilimab combined with IBI305 treatment group was significantly longer than that in the sorafenib treatment group (median PFS: 4.6 months vs. 2.8 months), and the adverse reactions were controllable, which is expected to be such Patients provide new treatment options.
As for second-line combination therapy, the CheckMate 040 study further explored the feasibility of nivolumab combined with ipilimumab  .
The tested patients received different doses of nivolumab and ipilimumab combination regimen, and the results showed that the combination regimen can achieve continuous objective relief and its safety is controllable.
The positive results of the study also contributed to the accelerated approval of the combination of nivolumab and ipilimumab for the treatment of advanced HCC in the United States.
Future prospects for treatment of advanced HCC
For the first-line treatment of advanced HCC, two Phase III clinical studies are ongoing, namely the COSMIC 312 study and the HIMALAYA study.
COSMIC 312 aims to evaluate the efficacy and safety of oral tyrosinase inhibitor (TKI) cabotinib combined with atilizumab versus sorafenib; the HIMALAYA study evaluated trimelimumab combined with duval Liyuzumab, contrast the effect of Vallizumab or Sorafenib in the treatment of HCC.
ImageIn addition, the current perioperative treatment is becoming more and more important, and the application of immune checkpoint inhibitors in HCC adjuvant therapy and neoadjuvant therapy is also being explored.
All in all, for inoperable HCC patients in the future, interdisciplinary systemic treatment is more needed.
How to select appropriate detection and prognostic biomarkers, screen the most benefiting patient groups, and formulate targeted and precise treatment strategies are all opportunities and challenges that need to be faced in the diagnosis and treatment of advanced HCC.
In addition, based on the benefit of the combination therapy, the dose, duration, and order of the administration need to be further adjusted in order to maximize the survival benefit.
Taking into account the etiology (viral hepatitis and non-viral pathogenic factors) factors, a more precise stratification of patients and the adoption of differentiated treatment may help to improve the treatment effect and weaken the side effects.
 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma［J］. J Hepatol, 2018, 69(1): 182-236.
 Biomarkers and Future Perspectives for Hepatocellular Carcinoma Immunotherapy. Front Oncol. 2021; 11: 716844.
 Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81-88. doi:10.1016/j.jhep.2013.02.022
 El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502. doi:10.1016/S0140-6736(17)31046-2
 Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial [published correction appears in Lancet Oncol. 2018 Sep;19(9):e440]. Lancet Oncol. 2018;19(7):940-952. doi:10.1016/S1470-2045(18)30351-6
 Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020;38(3):193-202. doi:10.1200/JCO.19.01307
 T. Yau, J.W. Park, R.S. Finn, et al. LBA38_PR – CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC), Annals of Oncology, Volume 30, Supplement 5, 2019
 Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745
 Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study [published correction appears in Lancet Oncol. 2021 Aug;22(8):e347]. Lancet Oncol. 2021;22(7):977-990. doi:10.1016/S1470-2045(21)00252-7
 Yau T, Kang YK, Kim TY, et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial [published correction appears in JAMA Oncol. 2021 Jan 1;7(1):140]. JAMA Oncol. 2020;6(11):e204564. doi:10.1001/jamaoncol.2020.4564
How many Immunotherapies for advanced hepatocellular carcinoma?
(source:internet, reference only)